Jinny Willis

Seasonality of birth and onset of clinical disease in children and adolescents (0-19 years) with type 1 diabetes mellitus in Canterbury, New Zealand.

AIMS To determine the seasonality of clinical disease onset and month of birth in type 1 diabetes mellitus (DM) in the southern hemisphere. PATIENTS Two hundred and seventy-five children with type 1 DM in the South Island of New Zealand were studied. The total live births (91,394) of the same period were used as control data. METHODS Seasonal rhythms were analyzed using the 12 month cosinor method. RESULTS The month of birth pattern of the patients with DM showed a statistically significant peak (p < 0.01) in summer, whereas the disease onset had a significant peak in winter (p < 0.01), similar to that registered in countries of the northern hemisphere, but in different months of the year. The total live births had no significant rhythm. The different seasonality of birth of the children who subsequently developed type 1 DM from that of the total live births is suggestive of the initiation of the autoimmune process in utero or perinatally.

Association of angiopoietin-2, C-reactive protein and markers of obesity and insulin resistance with survival outcome in colorectal cancer.

Background:This study investigated the relationship of obesity, insulin resistance, inflammation and angiogenesis with cancer progression and survival in a colorectal cancer cohort.Methods:Clinical and pathological data, along with anthropometric and follow-up data, were collected from 344 consecutive colorectal cancer patients. Serum samples at diagnosis were analysed by immunoassay for adiponectin, C-reactive protein (CRP), vascular endothelial growth factor-A (VEGF-A), angiopoietin-2 (Ang-2), insulin-like growth factor-1 (IGF-1), insulin and C-peptide.Results:Serum Ang-2 and VEGF-A levels increased with tumour T stage (P=0.007 and P=0.025, respectively) and N stage (P=0.02 and P=0.03, respectively), and correlated with CRP levels (r=0.43, P<0.001 and r=0.23, P<0.001, respectively). Angiopoietin-2 correlated with C-peptide (r=0.14, P=0.007) and VEGF-A with IGF-1 in males (r=0.25, P=0.001). Kaplan–Meier analysis showed that patients with high serum levels of CRP and Ang-2 had significantly reduced survival (both P⩽0.001). After adjusting for tumour stage and age, Ang-2 remained a significant predictor of survival. The CRP levels were inversely associated with survival in American Joint Committee on Cancer stage II patients (P=0.038), suggesting that CRP could be used to support treatment decisions in this subgroup. Serum markers and anthropometric measures of obesity correlated with each other, but not with survival.Conclusion:Our study supports the concept that obesity-related inflammation, rather than obesity itself, is associated with colorectal cancer progression and survival. The study confirms serum Ang-2 as a predictive marker for outcome of colorectal cancer.

Biovariability of plasma adiponectin.

Abstract Background: Adiponectin is a cytokine produced by adipose tissue with insulin sensitising and anti-atherosclerotic effects. Low plasma adiponectin levels are used as a marker of the metabolic syndrome and incipient type 2 diabetes. Methods: We carried out a series of studies to determine the short- and long-term variability of plasma adiponectin levels, including diurnal and post-prandial changes. These investigations also included examining the effect of frozen storage on plasma adiponectin levels. Results: A nested study in 10 overweight subjects with the metabolic syndrome and 10 age- and sex-matched controls showed intra-subject variation in adiponectin levels over a 30-day period of 12.2% and 18.8%, respectively, equivalent to reference change values of 1.7 and 3.6μg/mL. In non-obese subjects, plasma adiponectin levels varied minimally over a 15-month period (baseline, 8.3±2.9μg/mL vs. +15months, 8.2±3.0μg/mL, p=0.95) and showed only minor diurnal and post-prandial changes (pre-meal, 8.2±3.0μg/mL vs. 3h post-prandial, 8.3±3.1μg/mL, p=0.60). The adiponectin assay had an intra-assay variation of 8.8%, with storage at −30°C for 33months or three cycles of freezing and thawing having no discernible effect on adiponectin levels. Conclusions: These results demonstrate that plasma adiponectin levels have relatively low biovariability and that adiponectin can be sampled fasting or non-fasting to provide a reliable marker of insulin resistance and incipient type 2 diabetes. Clin Chem Lab Med 2006;44:1264–8.

Islet cell antibodies and antibodies against glutamic acid decarboxylase in newly diagnosed adult-onset diabetes mellitus

This study aimed to determine the prevalence of antibodies against glutamic acid decarboxylase (anti-GAD) and islet cell antibodies (ICA) in relation to beta-cell function in adults newly-diagnosed with diabetes mellitus. beta-cell function was assessed in adults aged 25-70 years newly-diagnosed with diabetes mellitus (n = 84) and control subjects (n = 34) using a 1.6 MJ mixed meal test procedure. beta-cell function was evaluated by the true insulin (defined as immunoreactive insulin minus proinsulin) response to the mixed meal test. Subjects were classified on the basis of the area under the true insulin curve (normal 16830-107700 pmol min/I) and the sum of the 30 and 60 min incremental response (normal 285-3295 pmol/I). The prevalence of anti-GAD and ICA was determined using radioimmunoprecipitation and indirect immunofluorescence, respectively. Twelve (14%) of the study cohort were insulin deficient showing little or no true insulin release. Of the insulin deficient individuals, seven (58%) subjects were anti-GAD antibody positive, compared with eleven (15%) of the subjects without insulin deficiency (P < 0.001). Seven (58%) insulin deficient subjects were ICA positive, whereas only two (3%) non-insulin deficient subjects were ICA positive (P < 0.001). Eight (67%) of the insulin deficient individuals had anti-GAD or ICA, compared with twelve (17%) of those who were not insulin deficient (P < 0.001). The positive predictive values for insulin deficiency of anti-GAD and ICA were 39 and 78% respectively. The sensitivity of both antibodies for detecting insulin deficiency was 50%. The specificity for detecting insulin deficiency was 85% for anti-GAD and 97% for ICA. Positivity for both anti-GAD and ICA gave a specificity and positive predictive value for insulin deficiency of 99%, and a sensitivity of 50%. Nearly one in seven adults presenting with diabetes mellitus as a new diagnosis are insulin deficient using our criteria. Loss of beta-cell function in two thirds of individuals who are insulin deficient can be identified by anti-GAD and ICA. Early detection of these immune markers of beta-cell damage creates the potential for immune modulation to limit such damage.

Cause-specific mortality in insulin-treated diabetic patients: A 20-year follow-up

BACKGROUND Diabetes is one of the most common chronic diseases in Western populations. There have been few large published cohort studies of diabetes with 20 years of follow-up worldwide, and none other than the present one in NZ. AIMS To establish cause-specific death rates, by age and sex in insulin-treated diabetic individuals living in Canterbury, NZ. METHODS Insulin-treated diabetic subjects on the Canterbury Diabetes Registry were followed over 20 years and vital status determined. Following notification of deaths, age- and sex-specific mortality rates, and sex-specific mortality ratios (SMRs) were calculated. RESULTS During follow-up 966 diabetic subjects contributed 13,495 person-years and 525 deaths occurred (261 females and 264 males). At all ages mortality rates were considerably higher than expected mortality. Relative mortalities were increased for cardiovascular (SMR women 3.73, 95% CI: 3.16-4.30; men 3.27, 95% CI: 2.76-3.78), renal (SMR women 5.55, 95% CI: 2.53-8.57; men 7.15, 95% CI: 3.40-10.90), respiratory disease (SMR women 3.31, 95% CI: 1.98-4.63; men 2.32, 95% CI: 1.41-3.23) and malignancy (SMR women 4.99, 95% CI: 2.99-6.99; men 2.19, 95% CI: 1.42-2.96) with cardiovascular disease accounting for the single greatest cause of excess death at all ages. CONCLUSIONS Mortality rates for diabetic individuals remain high, resulting in shortened life spans relative to the general population. To reduce these death rates attention must be paid to the early detection and treatment of CVD and associated risk factors.

Haemochromatosis gene mutations Cys282Tyr and His63Asp are not increased in Type 2 diabetic patients compared with the Canterbury (New Zealand) general population

Genetic predisposition to haemochromatosis may be an important aetiological factor in some cases of Type 2 diabetes. Our aim was therefore to test the hypothesis that the haemochromatosis gene mutations Cys282Tyr and His63Asp are more prevalent in Type 2 diabetic patients compared with the Canterbury, New Zealand general population. We studied 230 consecutive patients referred to the Diabetes Services with age > or = 30 years and considered to have Type 2 diabetes. DNA was extracted from whole blood and amplified by polymerase chain reaction prior to restriction fragment length polymorphism analysis. The frequency of the mutations was compared with that observed previously in 1064 subjects from the Canterbury general population by chi2 testing. Iron was measured by a colorimetric method, transferrin by rate nephelometry and ferritin by immunoassay. There were 2/230 (0.8%) Cys282Tyr homozygous subjects in the diabetic group compared with 5/1064 (0.5%) NS in the general population. Although there was a trend to lower incidence of Cys282Tyr heterozygosity in the diabetic group, there was no significant difference for any of the six genotype frequencies between the two groups. Haemochromatosis gene mutations Cys282Tyr and His63Asp are therefore not increased in Type 2 diabetics compared with the general population. Transferrin saturation was a sensitive marker (100%) of genetic haemochromatosis, although ferritin had low specificity (77.8%). Genetic susceptibility to haemochromatosis is not an important aetiological factor for diabetes, and targeted screening of diabetic patients for haemochromatosis is not indicated.

Incidence of type 1 diabetes mellitus diagnosed before age 20 years in Canterbury, New zealand over the last 30 years

This study examined the epidemiological characteristics of type 1 diabetes mellitus (DM) presenting in Canterbury, New Zealand, between 1970 and 1999. All patients with type 1 DM aged 0-19 years at diagnosis within the Canterbury geographical region were either admitted to the regional hospital or seen acutely as outpatients in clinics at the same institution. Primary ascertainment of incident cases, through notification by the attending physician or paediatrician, began prospectively in 1982. Incident cases between 1970 and 1982 were ascertained retrospectively from clinic and hospital records. For the years 1970-99, there were 474 incident cases (256 males, 218 females). Incidence rates determined from 5-yearly census population denominators ranged from 2.40 to 26.59 patients/100,000 person years. The mean for 5-year periods, starting from 1970, increased from 6.79 to 22.79 patients/100,000 person years, i.e. a 3.4-fold increase over 30 years. The increase in incidence based on linear regression of these data is 0.59 patients/100,000 per year, or an annual increase of 5% derived from regression of the natural logarithms of the incidence data. These observations are consistent with the increasing attack rates for type 1 DM reported worldwide.

Marginal effects of glucose, insulin and insulin‑like growth factor on chemotherapy response in endothelial and colorectal cancer cells

Resistance to chemotherapy is a major clinical issue for patients with colorectal cancer. Obesity has been associated with a poorer outcome and is a possible mechanism of resistance. The aim of the present study was to investigate the effect of obesity-related factors on the cell response to standard chemotherapy in stromal and colorectal cancer cells. Viability was measured following the treatment of colorectal cancer cell lines (WiDr and SW620) and stromal cells (human microvascular endothelial cells) in vitro with 5-fluorouracil, irinotecan and oxaliplatin under obesity-related conditions [elevated levels of insulin, insulin-like growth factor-1 (IGF-1) and glucose] and compared with non-elevated conditions. Obesity-related conditions alone increased cell viability and in selected cases, accumulation of the transcription factor, hypoxia-inducible factor-1. However, these conditions did not consistently increase resistance to the chemotherapy agents tested. The combination of IGF-1 and extremely low-dose chemotherapy significantly induced cell viability in WiDr colorectal cancer cells. These in vitro results may have clinical importance in an environment of increasing rates of obesity and colorectal cancer, and the frequent under-dosing of obese cancer patients.

Urban-rural variation in childhood type 1 diabetes incidence in Canterbury, New Zealand, 1980-2004

Geographical variation in the incidence of childhood type 1 diabetes is well documented. Such patterns are thought to give clues to the potential causes of this complex disease. This study examined the urban-rural differences in childhood type 1 diabetes in the Canterbury region of New Zealand between 1980 and 2004. We found significantly higher incidence of childhood type 1 diabetes in satellite urban communities, which could not be explained by the ethnic composition, neighbourhood deprivation, population density or household overcrowding in these areas. Varying levels of immigration and or/commuting in different urban-rural settings could explain this finding. This study highlights the value of geographical investigations for aetiological hypothesis generation.

CCR5 Genotyping in an Australian and New Zealand Type 1 Diabetes Cohort

Infiltration of pancreatic tissue by autoreactive T-cells involves secretion of multiple cytokines and chemokine receptor expression. Genetically determined variation in cell surface expression of the chemokine receptor CCR5 may result in differences in inflammatory cell migration in response to relevant chemokines. Adolescents with type 1 diabetes (T1D) from Australia and New Zealand were genotyped for CCR5-j 32 (n = 626). The allele frequency was compared with that of 253 non-diabetic Australian adolescents and with that of 92 adults with systemic lupus erythematosus. A reduced allele frequency was seen in T1D compared with controls (0.092 vs. 0.123, p = 0.05). This difference was not seen for the cohort of patients with SLE (freq=0.114). A reduction in the number of CCR5-j 32 / j 32 homozygotes, who lack CCR5, in the T1D cohort was also seen and while not statistically significant (2 observed compared to 5.25 expected; p = 0.12) is interesting. These results suggest a partial protection from T1D for CCR5-j 32 homozygous individuals is possible and that CCR5 has a potential role in the pathogenesis of T1D.